1. Field of the Invention
This invention relates to benzoxazine or enzothiazine derivatives which have cardiac stimulant activity by positive inotropic action. The compounds are useful in the treatment of cardiac disease in particular heart failure.
According to the present invention, there are provided novel benzoxazine or benzothiazine derivatives of the formula (A) and their pharmaceutically acceptable salts: ##STR2## wherein X and Y which are the same or different and represent oxygen or sulfur atom; R.sub.1, R.sub.2, and R.sub.3 which are the same or different and represent hydrogen atom, C.sub.1 -C.sub.4 lower alkyl group, or R.sub.1 and R.sub.2 may be connected to form a fused aromatic homocycle or heterocycle.
2. Description of Prior Arts
As drugs which increase myocardial contraction, that is, slow inotropic action, cardiac glycosides have been used for about past 200 years. However digitalis preparations have a narrow safety margin and also have a problem of insufficient curative effect.
As another class of positive inotrope, isoproterenol, dopamine and dobutamine which act on the sympathetic nervous system have been used. However, these drugs increase heart rate and have a risk of causing arrhythmia and moreover, have the disadvantage that they should be used in the form of i.v. injection. Therefore, the drugs are not proper for the treatment of chronic congestive heart failure (Drugs, 1987, 33, 503).
So, the study has been focused on drugs which show positive inotropic action, can be administered orally and have a broad safety margin.
In U.S. Pat. No. 4,728,653, a quinolone cardiac stimulant of the following general formula (1) ##STR3## wherein R.sub.1, R.sub.2 and R.sub.3 represent C.sub.1-4 lower alkyl group, lower alkoxy group, halogen atom, hydroxymethyl group or nitro group, and R.sub.4 represents C.sub.1-4 lower alkyl group or halogen atom is described.
The present inventors have carried out an intensive study and surprisingly found out that the novel benzoxazine or enzothiazine derivatives of formula (A) or salts thereof have a cardiac stimulant effect by positive inotropic action.